Rheumatic fever–associated Streptococcus pyogenes isolates aggregate collagen

Dinkla, Katrin; Rohde, Manfred; Jansen, Wim; Kaplan, Edward L.; Chhatwal, Gursharan S.; Talay, Susanne R.

doi:10.1172/jci17247

Cited by 106 publications

(86 citation statements)

References 43 publications

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“…It has previously been shown that streptococcal protein, causing rheumatic fever, binds to collagen type IV. Moreover, serum from patients with acute rheumatic fever contained increased titers of anti-collagen type IV antibodies [9]. In our study, IgM collagen type IV antibodies were present in 80% of the study population, whereas detectable levels of IgG were present in about 10% of the 747 individuals.…”

Section: Discussionsupporting

confidence: 42%

Autoantibodies against basement membrane collagen type IV are associated with myocardial infarction

McLeod

Dunér

Samnegård

et al. 2015

IJC Heart & Vasculature

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BackgroundCollagen type IV is the major constituent of basement membranes underlying endothelial cells and is important for endothelial cell attachment and function. Autoantibodies against native collagen type IV have been found in various autoimmune diseases. Oxidation of LDL in the vascular wall results in the formation of reactive aldehydes, which could modify surrounding matrix proteins. Like oxidized LDL, these modified matrix proteins are likely to induce immune responses. We examined whether autoantibodies against native or aldehyde-modified collagen type IV are associated with myocardial infarction.MethodsIgM and IgG against native and aldehyde-modified collagen type IV were measured by ELISA in serum from 387 survivors of a first myocardial infarction and 387 age- and sex-matched controls.ResultsPost-infarction patients had significantly increased levels of IgM against native collagen type IV, and IgG against native collagen type IV was present at detectable level in 17% of patients as opposed to 7% of controls (p < 0.001). Controlling for major cardiovascular risk factors demonstrated that the presence of IgG against native collagen type IV was associated with myocardial infarction (OR 2.9 (1.6–5.4), p = 0.001). Similarly, subjects in the highest quartile of IgM against native collagen type IV had increased risk of having suffered myocardial infarction (OR 3.11 (1.8–5.4), p < 0.001) after adjusting for cardiovascular risk factors. In contrast, IgG against aldehyde-modified collagen type IV was decreased in myocardial infarction patients, but this association was not independent of established cardiovascular risk factors.ConclusionAutoantibodies against collagen type IV are associated with myocardial infarction independently of traditional cardiovascular risk factors.

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Section: Discussionsupporting

confidence: 42%

Autoantibodies against basement membrane collagen type IV are associated with myocardial infarction

McLeod

Dunér

Samnegård

et al. 2015

IJC Heart & Vasculature

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“…These in vitro results are consistent with in vivo experimental and human clinical observations that have found autoantibodies against laminin, collagen IV (but not collagen I), B1AR, and CXAR as well as against myosin and actin in RHD and AM (39, 60–62, 78–85). In some cases, these antibodies recognize both laminin and cardiac myosin, mimicking the cross-reactivity observed in vitro here (81).…”

Section: Discussionsupporting

confidence: 90%

Rethinking Molecular Mimicry in Rheumatic Heart Disease and Autoimmune Myocarditis: Laminin, Collagen IV, CAR, and B1AR as Initial Targets of Disease

Root‐Bernstein

2014

Front. Pediatr.

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Rationale: Molecular mimicry theory (MMT) suggests that epitope mimicry between pathogens and human proteins can activate autoimmune disease. Group A streptococci (GAS) mimics human cardiac myosin in rheumatic heart disease (RHD) and coxsackie viruses (CX) mimic actin in autoimmune myocarditis (AM). But myosin and actin are immunologically inaccessible and unlikely initial targets. Extracellular cardiac proteins that mimic GAS and CX would be more likely.Objectives: To determine whether extracellular cardiac proteins such as coxsackie and adenovirus receptor (CAR), beta 1 adrenergic receptor (B1AR), CD55/DAF, laminin, and collagen IV mimic GAS, CX, and/or cardiac myosin or actin.Methods: BLAST 2.0 and LALIGN searches of the UniProt protein database were employed to identify potential molecular mimics. Quantitative enzyme-linked immunosorbent assay was used to measure antibody cross-reactivity.Measurements: Similarities were considered to be significant if a sequence contained at least 5 identical amino acids in 10. Antibodies were considered to be cross-reactive if the binding constant had a Kd less than 10-9 M.Main results: Group A streptococci mimics laminin, CAR, and myosin. CX mimics actin and collagen IV and B1AR. The similarity search results are mirrored by antibody cross-reactivities. Additionally, antibodies against laminin recognize antibodies against collagen IV; antibodies against actin recognize antibodies against myosin, and antibodies against GAS recognize antibodies against CX. Thus, there is both mimicry of extracellular proteins and antigenic complementarity between GAS-CX in RHD/AM.Conclusion: Rheumatic heart disease/AM may be due to combined infections of GAS with CX localized at cardiomyocytes that may produce a synergistic, hyperinflammatory response that cross-reacts with laminin, collagen IV, CAR, and/or B1AR. Epitope drift shifts the immune response to myosin and actin after cardiomyocytes become damaged.

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“…The most important of these would be proteins that GAS or CVB use to bind to cardiac myocytes, which are therefore complementary to, rather than mimics of, cardiac proteins. For example, Dinkla et al have identified an octapeptide from the GAS M protein that does not mimic cardiac myosin or induce antibodies crossreactive with cardiac myosin, but still produces rheumatic heart disease in animals [144–146]. Notably, this octapeptide binds to collagen IV on cardiomyocytes resulting in collagen IV autoantibodies.…”

Section: 4 Theoriesmentioning

confidence: 99%

Unresolved issues in theories of autoimmune disease using myocarditis as a framework

Root‐Bernstein

Fairweather

2015

Journal of Theoretical Biology

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Many theories of autoimmune disease have been proposed since the discovery that the immune system can attack the body. These theories include the hidden or cryptic antigen theory, modified antigen theory, T cell bypass, T cell-B cell mismatch, epitope spread or drift, the bystander effect, molecular mimicry, anti-idiotype theory, antigenic complementarity, and dual-affinity T cell receptors. We critically review these theories and relevant mathematical models as they apply to autoimmune myocarditis. All theories share the common assumption that autoimmune diseases are triggered by environmental factors such as infections or chemical exposure. Most, but not all, theories and mathematical models are unifactorial assuming single-agent causation of disease. Experimental and clinical evidence and mathematical models exist to support some aspects of most theories, but evidence/models that support one theory almost invariably supports other theories as well. More importantly, every theory (and every model) lacks the ability to account for some key autoimmune disease phenomena such as the fundamental roles of innate immunity, sex differences in disease susceptibility, the necessity for adjuvants in experimental animal models, and the often paradoxical effect of exposure timing and dose on disease induction. We argue that a more comprehensive and integrated theory of autoimmunity associated with new mathematical models is needed and suggest specific experimental and clinical tests for each major theory that might help to clarify how they relate to clinical disease and reveal how theories are related.

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Rheumatic fever–associated Streptococcus pyogenes isolates aggregate collagen

Cited by 106 publications

References 43 publications

Autoantibodies against basement membrane collagen type IV are associated with myocardial infarction

Autoantibodies against basement membrane collagen type IV are associated with myocardial infarction

Rethinking Molecular Mimicry in Rheumatic Heart Disease and Autoimmune Myocarditis: Laminin, Collagen IV, CAR, and B1AR as Initial Targets of Disease

Unresolved issues in theories of autoimmune disease using myocarditis as a framework

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